Compositions and methods for ameliorating pain

ABSTRACT

This invention is directed to compositions, methods and kits that can be used for the treatment or amelioration of pain.

This application claims priority from U.S. Provisional Application No.62/550,137 filed on Aug. 25, 2017, the entire contents of which isincorporated herein by reference.

All patents, patent applications and publications cited herein arehereby incorporated by reference in their entirety. The disclosures ofthese publications in their entireties are hereby incorporated byreference into this application in order to more fully describe thestate of the art as known to those skilled therein as of the date of theinvention described and claimed herein.

This patent disclosure contains material that is subject to copyrightprotection. The copyright owner has no objection to the facsimilereproduction by anyone of the patent document or the patent disclosureas it appears in the U S. Patent and Trademark Office patent file orrecords, but otherwise reserves any and all copyright rights.

GOVERNMENT INTERESTS

This invention was made with government support under Grant No. P30GM103340 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

FIELD OF THE INVENTION

This invention is directed to compositions, methods and kits that can beused for the treatment or amelioration of pain.

BACKGROUND OF THE INVENTION

For many types of pain (e.g., common headache, osteoarthritis)acetaminophen (ApAP, N-acetyl-para-aminophenol) has equal potency andefficacy to acetylsalicylic acid (aspirin). However, the safety of ApAPis a risk, particularly to a patient with impaired liver function.Overdose (inadvertent or for deliberate self-harm) or use in patientswith compromised liver function is the most common cause of fulminanthepatic failure in Western world (Bernal, Williams et al. “Acute liverfailure.” The Lancet 376.9736 (2010): 190-201). In these patients, acutefulminant hepatic failure presents are rapid development of hepaticdysfunction, leasing to encephalopathy, coagulopathy, and progressivemulti-organ failure.

ApAP overdose is the leading cause for calls to Poison Control Centersacross the United States with more than 100,000 annual calls and is theprimary reason for more than 56,000 emergency room visits and 2,600hospitalizations annually, resulting in an estimated 458 deaths due toacute liver failure in 2014 (Mercola, FDA Finally Changes PrescriptionRecommendations for High-Dose ApAP, 2014).

ApAP's toxicity is thought to be mediated via a toxic metabolite,N-acetyl-benzoquinoneimine (NAPQI) which depletes hepatic and renalgiutathione, a cytoprotective endogenous metabolite (Mason, R. P., andV. Fischer. Federation proceedings. Vol. 45. No. 10. 1986.; Mitchell etal., 1983). Hepatic toxicity with ApAP can occur at doses only 4- to8-fold higher than the maximum recommended analgesic dose (Neuberger etal., 1980); renal toxicity is rarely seen clinically. Pharmaceuticalcombinations that contain ApAP and a centrally acting analgesic can beeven more dangerous than ApAP alone. With repeated use thesecombinations require higher doses to produce the same analgesic effectbecause of an increase in tolerance. As the dose of the combination isincreased to compensate for analgesic tolerance, the safety of the drugdecreases as the higher doses of the ApAP component increase hepatictoxicity.

SUMMARY OF THE INVENTION

The present invention provides for analgesic compounds for treatingpain.

In some embodiments, the analgesic compound comprises a compound offormula (I):

wherein R comprises NH₂, N(CH₃)₂, NHCH₃, N(CH₂CH₃)₂, N₂(CH₂)₄CH₂C₆H₅,NH(CH₂)₂C₆H₅, NHCH₂C₆H₅, NO(CH₂)₄, NHCH₂CH₂CH₂CH₃, NHCH₂C₆H₄CH₃,NHCH₂C₆H₃Cl₂, NHCH₂C₆H₅CH₃, NHCH₂C₆H₅Cl, NHCH₂C₆H₅NO₂, NHC₅H₄,NHCH₂C(CH₃)₂, NHC(CH₃)₂, NHCH₂CH₂C₆H₃(OH)₂, NHCH₂C₆H₄N, NHCH₂C₆H3NCH₃,NHCH₂CH₂CH₂C₄H₄N, N(CH₃)CH₂CH₂OH, NHCH₂CH(OH)CH₂NH₂; or apharmaceutically acceptable salt thereof.

In some embodiments, the analgesic compound comprise a compound offormula (II):

wherein R¹ is H, OH, an alkyl group, a haloalkyl group, a halobenzylgroup, a phenyl group, —O-(alkyl), —O-(haloalkyl), —O-( halobenzyl),—O-(phenyl), an alkyl phenyl, a haloalkyl-phenyl, an alkyl-halobenzene,an alkyl-nitrobenzene, —O-(alkyl phenyl), —O-(haloalkyl)-phenyl, acycloalkane group, and wherein R² is selected from the group consistingof H and an alkyl group, or a pharmaceutically acceptable salt thereof.In some embodiments, R¹ comprises H, CH₃, (CH₂)₂C₆H₅, CH₂C₆H₅,CH₂CH₂CH₂CH₃, CH₂C₆H₃Cl₂, CH₂C₆H₅CH₃, CH₂C₆H₅Cl, CH₂C₆H₅NO₂, C₅H₄,CH₂C(CH₃)₂, C(CH₃)₂, CH₂CH₂C₆H₃(OH)₂, CH₂C₆H₄N, CH₂C₆H₃NCH₃,CH₂CH₂C₄H₄N, CH₂CH₂OH, or CH₂CH(OH)CH₂NH₂; and wherein R² is selectedfrom the group consisting of H and CH₃, or a pharmaceutically acceptablesalt thereof.

In some embodiments, alkyl can comprise C_(N)H_(2N-1), for example,wherein _(N) is 1-10.

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure;

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound comprises the followingchemical structure:

In some embodiments, the analgesic compound has a reduced risk ofhepatotoxicity when administered to a subject in vivo. For example, thecomposition can reduce the risk of hepatotoxicity by at least 5%, 10%,15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

In some embodiments, the analgesic con wound exhibits analgesiacomparable to ApAP when administered to a subject in vivo.

In some embodiments, the analgesic compound is a non-narcotic analgesic.

In some embodiments, the analgesic compound exhibits antipyreticactivity.

In some embodiments, the composition is not metabolized to NAPQI.

In some embodiments, the analgesic compound has a reduced risk ofhepatotoxicity, exhibits analgesia comparable to ApAP, is non-narcotic,exhibits antipyresis, and is not metabolized to NAPQI when administeredto a subject in vivo.

The present invention is further directed towards pharmaceuticalcompositions comprising an analgesic compound as described herein and asecond active ingredient, such as an opioid or an non-steroidalanti-inflammatory drug (NSAID). Non-limiting examples such opioidscomprise codeine, fenlanyl, hydrocodone, hydrocodone/ApAP,hydromorphine, meperidine, methadone, morphine, oxycodone, oxycodone andApAP, oxycodone and naloxone. Non-limiting examples of NSAIDs compriseaspirin, celecoxib, diclofenac, difiunisal, etodolac, ibuprofen,indontethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin,piroxicam, salsalate, sulindac, and tolmetin.

The present invention also provides for a method of treating pain in asubject.

The present invention further provides for a method of alleviating painin a subject.

Still further, the present invention provides for a method of preventingpain in a subject, reducing the incidence of pain in a subject, delayingthe development of pain in a subject, preventing the development of painin a subject, and/or palliating pain in a subject.

Non-limiting examples of such pain comprise acute pain, chronic pain,neuropathic pain, nociceptive pain, post-surgical pain, eye pain, dentalpain, and/or veterinary pain. In some embodiments, neuropathic paincomprises post-surgical pain, neuropathic pain, dental pain, ophthalmicpain, arthritic pain, post- and/or traumatic pain, or a combinationthereof.

In some embodiments, the method comprises administering to a subject inneed thereof a therapeutically effective amount of the analgesiccompound or composition as described herein. For example, thetherapeutically effective amount of the analgesic compound orcomposition administered to a subject can comprise a dose of about 10 μMto about 10 mM, or a dose of about 50 μM to about 1 mM.

In some embodiments, the analgesic compound or composition isadministered to a subject in a single dose, such as in a bolus. In otherembodiments, the compound is administered at intervals of about 4 hours,12 hours, or 24 hours. In still other embodiments, the compound isadministered continuously, such as in a drip IV infusion.

In some embodiments, the composition can be administered orally, such asin a pill, tablet, aqueous solution, or capsule; parentally, such as inan intravenous or intramuscular injection; transdermally, such as in acream, lotion, or patch; or nasally, such as in a spray. In otherembodiments, the composition can be administered subcutaneously,intrapulmonary, topically, intravitreally, transmucosally, rectally, andintranasally administration.

In some embodiments, the composition or analgesic compound as describedherein can be administered to a subject together with a therapeuticallyeffective amount of a second active ingredient, such as an opioid and/orNSAID. The second active ingredient can be administered prior to,concurrently with, or subsequent to the administration of a compositionor analgesic compound as described herein.

The present invention further provides a medical kit for the treatmentof pain. In embodiments, the kit comprises printed instructions foradministering the compound to the subject afflicted with pain and ananalgesic compound or composition as described herein.

Other objects and advantages of this invention will become readilyapparent from the ensuing description.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows analgesia of novel compounds SRP6D, R is comparable to ApAPin an in vivo mouse model utilizing two pain assays. A) Aceticacid-induced abdominal writhing assay. Number of abdominal stretches(writhes) induced by injection of acetic acid, n=7, p<0.05, SRP6D (n=5,p=0.022) and C) SRP6R (n=5, p=0.008) display analgesia compared tocontrol/vehicle only. B) Tail Hick assay. Percentage of maximumanalgesia for each mouse were calculated with the formula. PercentageAnalgesia=100*{[(Latency to tail flick after drug injection)−(Latency totail flick at baseline)]/[(12 sec cutoff time)−(Baseline latency)]}.Data expressed as mean±SEM, n=10.

FIG. 2 shows hepatotoxicity assays in primary human hepatocytes (hHEPs)reveal decreased toxicity for novel compounds SRP6D, R, compared to ApAPand to first generation saccharin ApAP derivatives, SCP-1 and SCP-1M.For example, doses tested were 500 μM ApAP, SCP1, SCP1M, SRP6D andSRP6R.

FIG. 3 shows hepatotoxicity assays in primary human hepatocytes (hHEPs),revealing decreased toxicity for novel compounds SRP6D and R, comparedto ApAP and to first generation saccharin ApAP derivatives, SCP-1 andSCP-1M. A) Lactate dehydrogenase (LDH) release is increased and B)reduced glutathione (GSH) is decreased in hHEPs in a time anddose-dependent manner for ApAP but not for SRP6D and R. Doses tested in(A) and (B) were 500 μM (0.5 mM) and 1000 μM (1 mM). C) A markedreduction in liver function tests is noted for the SRP6D and R, comparedto ApAP, the largest being in ALT. Dosage tested was 600 mg/kg.

FIG. 4 shows an antipyretic effect for the SRP compounds. Temperaturecurves demonstrate comparable antipyresis to ApAP for A) SRP6D and B)SRP6R in an LPS-induced fever mouse model. Note that 2, 8 and 10 h, theantipyresis is similar for ApAP, SRP6D and SRP6R. A Baker'syeast-induced fever demonstrates similar antipyretic effects of ApAP, C)SRP6D and D) SRP6R, n=10 per group. E) Pyrogenic dose of baker yeast(15% yeast. 0.1 ml/10 g body weight; control received ip injection ofvehicle, 0.9% saline) was done ip and temperatures were recorded at 4hours, after which, drugs were administered orally to febrile animalsbelonging to the treatment groups—(ApAP and SRP compounds at 300 mg/Kgbody weight). Two hours post injection, rectal temperatures determinedtotal change in body temperature. Data expressed as mean±SEM, n=10.

FIG. 5 shows favorable cytochrome P450 metabolism for SRP6D and SRP6R invarious P450 isoenzymes. Red hash mark demonstrates the effect of ApAPand green hash mark denotes the first generation saccharin derivative ofApAP. Top panels are enzyme activities in relative fluorescence unitsand bottom panels are percent enzymatic activity.

FIG. 6 shows standard curves for liver function tests (LFTs) for SRPcompounds.

FIG. 7 shows liver function assays. (ALT, AST and ALP) were run afterdosing CDI male mice with 600 mg/kg of compounds—SRP compounds and APAPvia PO (per os) (gavage). The assays were run with serum collected frommice injected with compounds or vehicle, after overnight (15 hours)fasting. After drug administration, water and food were provided to themice ad libitum. The results showed increased levels of liver enzymeactivity for APAP while, the other compounds were similar to thevehicle. LFT levels for the SRP compounds did not reach APAP levels.

FIG. 8 shows chemical embodiments of the invention.

FIG. 9 shows functional assay to determine blood creatinine levels wererun after dosing CDI male mice with 600 mg/Kg (body weight) of compoundsSRP compounds and APAP via PO (per os) (gavage). The assays were runwith serum collected from mice injected with compounds or vehicle, afterovernight (15 hours) fasting. After drug administration, water and foodwere provided to the mice ad libitum. The results showed increasedlevels of creatinine for APAP while. SRP6D was similar to the vehicle.LFT levels for the other SRP compounds did not reach APAP levels.

FIG. 10 is a bar graph showing the distribution of calculated logPvalues of more than 3000 drugs on the market.

FIG. 11 is a bar graph showing results from gas chromatography used todetect a toxic metabolite, N-acetyl-benzoquinoneimine (NAPQI). Peak at5.788.

DETAILED DESCRIPTION OF THE INVENTION

Abbreviations and Definitions

Detailed descriptions of one or more embodiments are provided herein. Itis to be understood, however, that the present invention can be embodiedin various forms. Therefore, specific details disclosed herein are notto be interpreted as limiting, but rather as a basis for the claims andas a representative basis for teaching one skilled in the art to employthe present invention in any appropriate manner.

The singular forms “a”, “an” and “the” include plural reference unlessthe context clearly dictates otherwise. The use of the word “a” or “an”when used in conjunction with the term “comprising” in the claims and/orthe specification can mean “one,” but it is also consistent with themeaning of “one or more.” “at least one,” and “one or more than one.”

Wherever any of the phrases “for example,” “such as,” “including” andthe like are used herein, the phrase “and without limitation” isunderstood to follow unless explicitly stated otherwise. Similarly “anexample,” “exemplary” and the like are understood to be nonlimiting.

The term “substantially” allows for deviations from the descriptor thatdo not negatively impact the intended purpose. Descriptive terms areunderstood to be modified by the term “substantially” even if the word“substantially” is not explicitly recited.

The terms “comprising” and “including” and “having” and “involving” (andsimilarly “comprises”, “includes,” “has,” and “involves”) and the likeare used interchangeably and have the same meaning. Specifically, eachof the terms is defined consistent with the common United States patentlaw definition of “comprising” and is therefore interpreted to be anopen term meaning “at least the following,” and is also interpreted notto exclude additional features, limitations, aspects, etc. Thus, forexample, “a process involving steps a, b, and c” means that the processincludes at least steps a, b and c. Wherever the terms “a” or “an” areused, “one or more” is understood, unless such interpretation isnonsensical in context.

As used herein, the term “about” can refer to approximately, roughly,around, or in the region of. When the term “about” is used inconjunction with a numerical range, it modifies that range by extendingthe boundaries above and below the numerical values set forth. Ingeneral, the term “about” is used herein to modify a numerical valueabove and below the stated value by a variance of 20 percent up or down(higher or lower).

Analgesic Compounds

Aspects of the invention are directed towards analgesic compounds andcompositions comprising the analgesic compounds. The term “analgesic” or“analgesia” can refer to an agent that lessens, alleviates, reduces,relieves, or extinguishes pain in an area of a subject's body.

Further, aspects of the invention are directed towards compounds and/orcompositions that exhibit antipyrisis. For example, analgesic compoundsas described herein can be considered “antipyretics” or “antipyreticcompounds,” which can refer to a compound or composition that has theability to reduce the subject's body temperature, such as tophysiologically normal levels, when the subject has an abnormally highbody temperature (e.g., fever). Antipyretic compounds, such as thosedescribed herein, can also block the onset of fever.

Embodiments of the invention demonstrate analgesic and/or antipyreticproperties while having no or reduced levels of hepatotoxicity. The term“hepatotoxicity” can refer to the chemical- or drug-induced liverdamage. Drug-induced liver injury or damage is a cause of acute orchronic liver disease. Hepatotoxicity can be caused by certain medicinalagents, when taken in overdoses or sometimes even when introduced withintherapeutic ranges.

ApAP is usually well tolerated in prescribed dose, but overdose is acommon cause of drug-induced liver disease and acute liver failure.Damage to the liver is not due to the drug itself but to a toxicmetabolite (N-acetyl-p-benzoquinone imine (NAPQI)) produced bycytochrome P-450 enzymes in the liver. In normal circumstances, thismetabolite is detoxified by conjugating with glutathione in phase 2reaction. In an overdose, a large amount of NAPQI is generated, whichoverwhelms the detoxification process and leads to liver cell damage.Nitric oxide also plays a role in inducing toxicity. The risk of liverinjury is influenced by several factors, such as the dose ingested,concurrent alcohol or other drug intake, and/or interval betweeningestion and antidote. The dose toxic to the liver is quite variablefrom person to person and is often thought to be lower in chronicalcoholics. Measurement of blood level is important in assessingprognosis, wherein higher levels predicting a worse prognosis. Thosethat develop acute liver failure can still recover spontaneously, butcan require transplantation if poor prognostic signs such encephalopathyor coagulopathy is present.

In some embodiments, the analgesic compound or composition comprisingthe same has a reduced risk of hepatotoxicity, for example when comparedto ApAP, when administered to a subject in vivo. For example, thecomposition can reduce the risk of hepatotoxicity by at least 5%, 10%,15%, 20%, 25%, 35%, 40%, 45%, or 50%.

In some embodiments, the analgesic compound comprises formula (I):

In other embodiments, R comprises NH₂, N(CH₃)₂, NHCH₃, N(CH₂CH₃)₂,N₂(CH₂)₄CH₂C₆H₅, NH(CH₂)₂C₆H₅, NHCH₂C₆H₅, NO(CH₂)₄, NHCH₂CH₂CH₂CH₃,NHCH₂C₆H₄CH₃, NHCH₂C₆H₃Cl₂, NHCH₂C₆H₅CH₃, NHCH₂C₆H₅Cl, NHCH₂C₆H₅NO₂,NHC₅H₄, NHCH₂C(CH₃)₂, NHC(CH₃)₂, NHCH₂CH₂C₆H₃(OH)₂, NHCH₂C₆H₄N,NHCH₂C₆H3NCH₃, NHCH₂CH₂C₄H₄N, N(CH₃)CH₂CH₂OH, NHCH₂CH(OH)CH₂NH₂; or apharmaceutically acceptable salt thereof.

In some embodiments, the analgesic compound comprises formula (II):

In some embodiments, R¹ can be H, OH, an alkyl group, a halogen group, ahaloalkyl group, a halobenzyl group, a phenyl group, —O-(alkyl),—O-(haloalkyl), —O-(phenyl), —O-(halobenzyl), an alkyl phenyl, ahaloalkyl-phenyl, an alkyl-halobenzene, an alkyl-nitrobenzene, —O-(alkylphenyl), —O-(haloalkyl-phenyl, a cycloalkane group. In furtherembodiments, the alkyl group comprises C1-C2 carbon chains, C1-C3 carbonchains, C1-C4 carbon chains, C1-C5 carbon chains, C1-C6 carbon chains,C1-C7 carbon chains, C1-C8 carbon chains, C1-C9 carbon chains, C1-C10carbon chains. In other embodiments, the alkyl group can be C1-C4 carbonchains. In some embodiments, the halogen can be F, Br, Cl. In someembodiments, the cycloalkane group can be a 5-member ring. In someembodiments, the cycloalkane group can be a 6-member ring. In someembodiments, the analgesic compound described herein is pharmaceuticallyacceptable salt.

In yet other embodiments, R¹ can be H, OH, an alkyl group, a halogengroup, a haloalkyl group, a haloben/yl group, a phenyl group,—O-(alkyl), —O-(haloalkyl), —O-(phenyl), —O-(halobenzyl), an alkylphenyl, a haloalkyl-phenyl, an alkyl-halobenzene, an alkyl-nitrobenzene,—O-(alkyl phenyl), —O-(haloalkyl)-phenyl, a cycloalkane group. Infurther embodiments, the alkyl group comprises C1-C2 carbon chains,C1-C3 carbon chains, C1-C4 carbon chains, C1-C5 carbon chains, C1-C6carbon chains, C1-C7 carbon chains, C1-C8 carbon chains. C1-C9 carbonchains, C1-C10 carbon chains. In other embodiments, the alkyl group canbe C1-C4 carbon chains. In some embodiments, the halogen can be F, Br,Cl. In some embodiments, the cycloalkane group can be a 5-member ring.In some embodiments, the cycloalkane group can be a 6-member ring. Insome embodiments, the analgesic compound described herein ispharmaceutically acceptable salt.

In further embodiments, R¹ comprises H, CH₃, (CH₂)₂C₆H₅, CH₂C₆H₅,CH₂CH₂CH₂CH₃, CH₂C₆H₅Cl₂, CH₂C₆H₅CH₅, CH₂C₆H₅Cl, CH₂C₆H₅NO₂, C₅H₄,CH₂C(CH₃)₂, C(CH₃)₂, CH₂CH₂C₆H₅(OH)₂, CH₂C₆H₄N, CH₂C₆H₃NCH₃,CH₂CH₂C₄H₄N, CH₂CH₂OH, or CH₂CH(OH)CH₂NH₂; and R² is selected from thegroup consisting of H and CH₃; or a pharmaceutically acceptable saltthereof.

Non-limiting examples of analgesic compounds of the inventions are shownin Table 1 below. As desired, such compounds can also be provided assalts thereof.

TABLE 1 Mol Identifier STRUCTURE weight cLog P SRP6a

349.36 0.26 SRP6b

377.41 0.71 SRP6c

363.39 0.49 SRP6d

405.47 1.42 SRP6e

508.59 2.28 SRP6f

453.51 2.50 SRP6g

439.48 2.21 SRP6h

419.45 0.49 SRP6i

405.47 1.81 SRP6j

469.51 2.05 SRP6k

508.37 3.42 SRP6l

453.51 2.72 SRP6m

473.93 2.81 SRP6n

484.48 2.75 SRP6o

417.48 1.84 SRP6p

405.47 1.73 SRP6q

391.44 1.26 SRP6r

485.51 1.89 SRP6s

440.47 1.07 SRP6t

440.47 2.39 SRP6u

446.52 0.60 SRP6w

SRP6x

SCP1

332.33 1.28 SCP1M (SCP-1 metabolite)

350.35 From 1.07 to −2.48  

The logP value of a compound is a measure of the compound'shydrophilicity. The log value of a compound, which is the logarithm ofits partition coefficient between n-octanol and waterlog(c_(octanol)/c_(water)), is a measure of the compound'shydrophilicity. Typically, a low solubility contributes to poorabsorption. Low hydrophilicities are indicated by high logP. High logPvalues can indicate poor absorption or permeation. Low Calculated Log P(cLog P) values can indicate compounds with shorter half-lives and poorabsorption. Low hydrophilicities and therefore high logP values causepoor absorption or permeation. Without being bound by theory, forcompounds to have a reasonable probability of being well absorbed, theirlogP value must not be greater than 5.0. Exemplary embodiments comprisecompounds with intermediate cLog P values, such as about 1, 1.2, 1.4,1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, or 3. In some embodiments, the cLog Pvalue of a compound is about 2.0. Embodiments can also comprise acompound with a logP value of no greater than about 5.0. Thedistribution of calculated logP values of more than 3000 drugs on themarket is shown in FIG. 10 [source:http://www.opeamolecules.org/properties/properties.html.]

Pain

Embodiments can be used for the treatment or amelioration of pain,non-limiting examples of which comprise post-surgical, neuropathic,dental, ophthalmic, arthritic, post- and/or traumatic pain.

The term “pain” can refer to all types of pain. For example, the termcan refer to acute pains and chronic pains, such as neuropathic painarid post-operative/post-surgical pain, chronic lower back pain,ophthalmic pain, arthritic pain, post-traumatic pain, traumatic pain,cluster headaches, herpes neuralgia, phantom limb pain, central pain,dental pain, opioid-resistant pain, visceral pain, surgical pain, boneinjury pain, pain during labor and delivery, pain resulting from burns,including sunburn, post-partum pain, migraine, angina pain, andnenitourinary tract-related pain including cystitis. The term can alsorefer to nociceptive pain or nociception, such as somatic pain (normalnerve response to a noxious stimulus). Pain can also refer to pain thatis categorized temporally, e.g., chronic pain and acute pain; pain thatis categorized in terms of its severity, e.g., mild, anodente, orsevere; and pain that is a symptom or a result of a disease state orsyndrome, e.g., inflammatory pain, cancer pain, AIDS pain, arthropathy,migraine, trigeminal neuralgia, cardiac ischaemia, and diabeticneuropathy (see, e.g., Harrison's Principles of Internal Medicine, pp,93-98 (Wilson et al., eds. 12th ed. 1991), Williams et al. J. ofMedicinal Chem. 42:1481-1485 (1999), herein each incorporated byreference in their entirety).

“Neuropathic pain” (NP) can refer to a type of chronic pain thatfrequently develops following an injury or disease of either nerve orperipheral tissue. Neuropathic pain (NP) can develop with ongoing,spontaneous, paroxysmal, and lancinating pain components. Such NP isalmost invariably associated with abnormalities of cutaneous sensibilityin the forms of allodynia (sensation of pain from stimuli that are notnormally painful), hyperalgesia (increased sensation to normally painfulstimuli), and dysesthesis (unpleasant abnormal sensation). Althoughknowledge about neuropathic pain mechanisms has advanced tremendously,satisfactory treatment options for NP have been elusive.

Neuropathic pain according to the present disclosure can be divided into“peripheral” (originating in the peripheral nervous system) and“central” (originating in the brain or spinal cord).

The features of neuropathic pain are known to be different from that ofthe general, nociceptive type of pain. Nociceptive type of pain canrefer to a chronic or acute pain associated with a painful stimulus.Most animal models used to study pain and its treatment are based on thenocieeptive type of pain, e.g., tail flick or hot plate models.Neuropathic pain can be induced by innocuous stimuli, and responds muchless to some medications than does the nociceptive type. For example,opioids seldom have an analgesic effect on neuropathic pain, whileopioids are successful in producing an analgesic effect on nociceptivepain. Neuropathic pain can result from peripheral nerve trauma (erg.,amputation), infection (e.g., post-herpetic neuralgia), infarct, ormetabolic disturbance (e.g., diabetic neuralgia). New treatmentstrategies are needed for treatment of neuropathic pain.

“Dental pain” can refer to pain felt in the mouth area, such as gums,teeth, and/or jaw. Dental pain can indicate an oral health problem, suchas gum disease, tooth decay or TMJ disorder, although the pain can alsobe caused by conditions that are not dental in nature, such as sinus orear infections or heart problems.

In most cases, dental pain can be caused be or can result from to toothdecay. When a cavity gets larger, it begins to irritate the pulp, whichis the center of the tooth that contains nerves and blood vessels. Thepulp can also be irritated when the tooth is touched or comes intocontact with cold, hot or very sweet food and beverages. In advancedcases of tooth decay, destruction of the enamel and dentin (the middlelayer of the tooth) can allow bacteria to invade the pulp, which canlead to infection and result in tooth abscess. Whenever the pulp becomesirritated, its nerves send signals to the brain, causing pain. Althoughthe pain can sometimes dissipate over time without any treatment, thecondition will continue to worsen and the pain can return if the tissueand bone surrounding the affected tooth becomes infected.

Gingivitis can also be the cause of dental pain. The soft tissue of thegums can become inflamed because of the build-up of plaque along the gumline. As a result, gums loosen and detach from the teeth, forming deeppockets of space between the gums and teeth. Bacteria invade thesepockets, causing swelling, bleeding and pain. In severe cases, whenbacteria dissolve the bone surrounding tooth roots, tooth and bone losscan occur. When the roots of teeth become exposed due to receding gumsor bone loss, tooth sensitivity can result. Nerve endings contained inthe lower part of the tooth react to certain stimuli, such as cold air,food or drinks, causing dental pain.

Dental pain can also occur in the jaw area and can be caused by, forexample, muscle strain. The muscles controlling the temporomandibularjoint (TMJ) can spasm and trigger pain. This often happens in patientswith an unstable bite, missing or improperly aligned teeth.

The additional oral symptoms that can be related to dental pain dependon its cause, non-limiting examples of which comprise sensitivity tocertain stimuli (e.g., cold, heat, air, biting, chewing), loose teeth,bad breath (halitosis), red and/or swollen gums, bleeding gums, recedinggums, difficulty opening or closing the mouth, cracking sound when jawopens, foul-tasting discharge, and/or pus near the source of the pain.Furthermore, symptoms in other areas of the body can appear along withdental pain, non-limiting examples of which comprise fever, headachesand difficulty swallowing or breathing.

Dental pain can he due to a variety of medical conditions, non-limitingexamples of which comprise tooth decay, gum disease, debris,temporomandibular joint (TMJ) disorder, and/or teeth grinding (bruxism).Other causes of dental pain comprise tooth eruption, such as inchildren, or tooth impaction; fractured, cracked or broken teeth;exposed tooth root; dry socket (complication of tooth extraction);trauma to head or teeth; abnormal bite; recent dental work; and or methmouth (caused by use of methamphetamine). Further, dental pain can alsobe the result of a condition elsewhere in the body, such as earinfection, sinus infection, migraines, heart problems (such as pain thatincreases with exertion), neurological conditions (e.g., trigeminalneuralgia), burning mouth syndrome, and/or salivary gland dysfunction.

“Ophthalmic pain” or “eye pain,” also known as ophthalmalgia can fallinto one of two categories: ocular pain which occurs on the eye'ssurface, and/or orbital pain which occurs within the eye.

Eye pain that occurs on the surface can be a scratching, burning, oritching sensation. Surface pain can be caused by irritation from aforeign object, infection, or trauma.

Eye pain that occurs deeper within the eye can be aching, gritty,stabbing, or throbbing.

Eye pain can be accompanied by vision loss.

Ophthalmic pain, which occurs on the eye's surface, can be caused by,for example, a foreign object, conjunctivitis, contact lens irritation,corneal abrasion, injury, chemical burns and flash bums to the eye,blepharitis, and/or a sty.

Ophthalmic pain that occurs within the eye (e.g. orbital pain) can becaused by glaucoma, optic neuritis, sinusitis, migraines, injury,iritis, and/or inflammation of the eye.

“Arthritic pain” can refer to any pain arising anatomically from thejoints and their adjacent bones and non-osseous tissues. Any arthriticpain can be treated by the invention including, without limitation, anypain resulting from an auto-immune, infectious, inflammatory,proliferative, regenerative or degenerative process so involving thejoints of an animal or human patient. As such, suitable pain treatablewith the current invention includes pain from rheumatoid or osteoarthritis.

“Post-surgical pain” (interchangeably termed “post-incisional” or“post-traumatic pain”) can refer to pain arising or resulting from anexternal trauma such as a cut, puncture, incision, tear, or wound intotissue of an individual (including that that arises from all surgicalprocedures, whether invasive or non-invasive).

In some embodiments, post-surgical pain is internal or external(including peripheral) pain, and the wound, cut, trauma, tear orincision can occur accidentally (as with a traumatic wound) ordeliberately (as with a surgical incision).

Post-surgical pain, as used herein, includes allodynia (i.e., increasedresponse (i.e., a noxious perception) to a normally non-noxiousstimulus) and hyperalgesia (i.e., increased response to a normallynoxious or unpleasant stimulus), which can in turn, be thermal ormechanical (tactile) in nature. In some embodiments, the post-surgicalpain is characterized by thermal sensitivity, mechanical sensitivityand/or resting pain. In some embodiments, the post-surgical paincomprises mechanically-induced pain or resting pain. In otherembodiments, the post-surgical pain comprises resting pain.

Pharmaceutical Combinations

Embodiments comprise structural analogs of ApAP molecules that functionas non-toxic, non-addictive, non-narcotic pain relievers. Such compoundscan be a component of pharmaceutical combinations for the treatment oramelioration of pain.

The pharmaceutical combinations of the present invention compriseanalgesics as described herein, such as SRP6D and SRP6R, in an admixturewith an analgesic as described herein along with a pharmaceuticallyacceptable carrier prepared according to conventional pharmaceuticaltechniques. According to the invention, a pharmaceutically acceptablecarrier can comprise any and all solvents, dispersion media, coatings,antibacterial and anti fungal agents, isotonic and absorption delayingagents, and the like, compatible with pharmaceutical administration. Theuse of such media and agents for pharmaceutically active substances iswell known in the art. Non-limiting examples of pharmaceuticallyacceptable carriers comprise solid or liquid fillers, diluents, andencapsulating substances, including but not limited to lactose,dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol,starches, gum acacia, alginate, gelatin, calcium phosphate, calciumsilicate, cellulose, methyl cellulose, microcry stalline cellulose,polyvinylpyrrolidone, water, methyl benzoate, propyl benzoate, talc,magnesium stearate, and mineral oil. The amount of the carrier employedin conjunction with the combination is sufficient to provide a practicalquantity of material per unit dose of analgesic.

The use of such media and agents for pharmaceutically active substancesis well known in the art. Any conventional media or agent that iscompatible with the active compound can be used. Supplementary activecompounds can also be incorporated into the compositions.

Pharmaceutically acceptable carriers for oral administration comprisesugars, starches, cellulose and its derivatives, malt, gelatin, talc,calcium sulfate, vegetable oils, synthetic oils, polyols, algmic acid,phosphate buffer solutions, emulsifiers, isotonic saline, andpyrogen-free water. Pharmaceutically acceptable carriers for parenteraladministration comprise isotonic saline, propylene glycol, ethyl oleale.pyrrolidone, aqueous ethanol, sesame oil, corn oil, and combinationsthereof.

Various oral dosages forms can be employed, non-limiting examples ofwhich comprise solid forms such as tablets, capsules, granules,suppositories and or powders. Tablets can be compressed, tablettriturates, enteric-coated, sugar-coated, film-coated or multiplecompressed, containing suitable binders, lubricants, diluents,disintegrating agents, coloring agents, flavoring agents, flow-inducingagents, and melting agents. Liquid oral dosage forms comprise aqueoussolutions, emulsions, suspensions, syrups, aerosols and/or reconstitutedsolutions and or suspensions. The composition can alternatively beformulated for external topical application, or in the form of a sterileinjectable solution.

Pharmaceutically effective combinations can be provided as a compositioncomprising between 0.1 and 2000 mg/kg of an analgesic as describedherein, such as SRP6D and SRP6R. For example, pharmaceutically effectivecombinations can be provided as a composition comprising about 0.1mg/kg, 1 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 60mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg,175 mg/kg, 200 mg/kg, 225 mg/kg, 250 mg/kg, 275 mg/kg, 300 mg/kg, 325mg/kg, 350 mg/kg, 375 mg/kg, 400 mg/kg, 425 mg/kg, 450 mg/kg, 475 mg/kg,500 mg/kg, 525 mg/kg, 550 mg/kg, 575 mg/kg, 600 mg/kg, 625 mg/kg, 650mg/kg, 675 mg/kg, 700 mg/kg, 725 mg/kg, 750 mg/kg, 775 mg/kg, 800 mg/kg,825 mg/kg, 850 mg/kg, 875 mg/kg, 900 mg/kg, 925 mg/kg, 950 mg/kg, 975mg/kg, 1000 mg/kg, 1100 mg/kg, 1200 mg/kg, 1300 mg/kg, 1400 mg/kg, 1500mg/kg, 1600 mg/kg, 1700 mg/kg, 1800 mg/kg, 1900 mg/kg, 2000 mg/kg of ananalgesic. Useful pharmaceutically effective combinations can containbetween about 300 mg/kg and about 1000 mg/kg of an analgesic asdescribed herein, such as SRP6D and SRP6R. For example, embodiments asdescribed herein can comprise about 300 mg/kg of an analgesic.

Pharmaceutically effective combinations, such as a pill or tablet, canbe comprise between 0.1 and 2000 mg of an analgesic as described herein,such as SRP6D and SRP6R. For example, pharmaceutically effectivecombinations can comprise about 0.1 mg, 1 mg, 10 mg, 20 mg, 30 mg, 40mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg. 175 mg,200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg,425 mg, 450 mg, 475 mg. 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg,650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg,875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1100 mg, 1200 mg, 1300mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg of ananalgesic. Useful pharmaceutically effective combinations can containbetween about 300 mg and about 1000 mg of an analgesic as describedherein, such as SRP6D and SRP6R. For example, embodiments as describedherein can comprise about 300 mg of an analgesic.

The present invention also comprises the formation of pharmaceuticallyacceptable, stable salts of the compounds as described herein, such asSRP6D and SRP6R, with metals or amines. Non-limiting examples of metalsused as cations comprise alkali metals such as Na⁺ or K⁺ andalkaline-earth metals such as Mg²⁺ and Ca²⁺. Non-limiting examples ofamines comprise N,N-dibenzylethylenediamme, chloro-procaine, choline,diethanolamine, ethylenediamine, N-methylglueamine and procaine.

A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral (e.g., inhalation), transdermal (topical),(transmucosal, and rectal administration. Solutions or suspensions usedfor parenteral, intradermal, or subcutaneous application can include thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. pH can beadjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

As an exemplary embodiment, pharmaceutical combinations of the inventioncan be administered orally, either in the form of tablets containingexcipients such as starch or lactose, or in capsules, either alone ormixed with excipients, or in the form of syrups or suspensionscontaining coloring or flavoring agents. They can also be injectedparenterally, for example intramuscularly, intravenously orsubcutaneously. In parenteral administration, they can be used in theform of a sterile aqueous solution which can contain other solutes, suchas, for example, any salt or glucose in order to make the solutionisotonic.

The compounds of the present invention can be administered to a subjectfor the treatment of pain, for example orally, either covered in gelatincapsules or compressed in lozenges. For oral therapeutic administration,said compounds can be mixed with excipients and used in the form oflozenges, tablets, capsules, elixirs, suspensions, syrups, wafers,chewing gum, and the like. These preparations could contain at least0.5% of active compound, but can vary depending on each form, inparticular between 4% and 75% approximately of the weight of each unit.The amount of active compound in such compositions should be that whichis necessary for obtaining the corresponding dosage. For example, thecompositions and preparations as described herein can be prepared insuch a way that each oral dosage unit can contain between 0.1 mg and 300mg of the active compound.

In parenteral therapeutic administration, the active compounds of thisinvention can be incorporated in a solution or suspension. Suchpreparations, for example, can contain at least 0.1% of the activecompound, but can vary between 0.5% and 50% approximately of the weightof the preparation. For example, such preparations comprise about 0.1%,0.5%, 1%, 5%, 10%, 15%, 25%, 30%, 35%, 40%, 45%, 50%, of the weight ofthe preparation. The amount of active compound in such compositionsshould be that which is necessary for obtaining the correspondingdosage. The compositions and preparations as described herein can beprepared in such a way that each parenteral dosage unit can containbetween 0.01 to and 1000 mg for example between about 0.5mg and 100 mgof the active compound, for example. While intramuscular administrationcan be given in a single dose or divided into up to multiple doses, suchas three doses, intravenous administration can include a drip device forgiving the dose by venoclysis. Parenteral administration can beperformed by means of ampoules, disposable syringes or multiple-dosevials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use can includesterile aqueous solutions (where water soluble) or dispersions andsterile powders for the extemporaneous preparation of sterile injectablesolutions or dispersions. For intravenous administration, suitablecarriers can include physiological saline, bacteriostatic water,Crernophor EM™ (BASF, Parsippany, N.J.) or phosphate buffered saline(PBS). In embodiments, the composition can be sterile and should befluid to the extent that easy syringability exists. It can be stableunder the conditions of manufacture and storage and can be preservedagainst the contaminating action of microorganisms such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing forexample, water, ethanol, a pharmaceutically acceptable polyol likeglycerol, propylene glycol, liquid polyetheylene glycol, and suitablemixtures thereof. The proper fluidity can be maintained, for example, bythe use of a coating such as lecithin, by the maintenance of therequired particle size in the case of dispersion and by the use ofsurfactants. Prevention of the action of microorganisms can be achievedby various antibacterial and antifungal agents, for example, pambens,chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, itcan be useful to include isotonic agents, for example, sugars,polyalcohols such as in mannitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions canoccur by including an agent in the composition which delays absorption,for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating thecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated herein, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle which containsa basic dispersion medium and the required other ingredients from thoseenumerated herein. In the case of sterile powders for the preparation ofsterile injectable solutions, examples of useful preparation methods arevacuum drying and freeze-drying which yields a powder of the activeingredient plus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an ediblecarrier. They can be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches, or capsules. Oral compositions can also be preparedusing a fluid carrier for use as a mouthwash, wherein the compound inthe fluid carrier is applied orally and swished and expectorated orswallowed.

Pharmaceutically compatible binding agents, and/or adjuvant materialscan be included as part of the composition. The tablets, pills,capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such, asmicrocrystalline cellulose, gum tragacanth or gelatin, an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orsterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

The compounds of the present invention can be administered to a subjectfor the treatment of pain in a single dose, or as multiple doses over aperiod of time. Further, the compound can be administered at intervalsof about 4 hours, 8 hours, 12 hours, 24 hours, or longer. For example, apill can be administered to a subject prior to the onset of pain toprevent pain, or a multiple pills can be administered over a period oftime to ameliorate pain over said period.

Of necessity, there will be variations which will depend on the weightand conditions of the subject to be treated and on the particularadministration route selected.

Methods of Treatment

Embodiments can be used for the treatment or amelioration of pain,non-limiting examples of which comprise post-surgical, neuropathic,dental, ophthalmic, arthritic, post- and/or traumatic pain.

In embodiments, a compound as described herein, such as SRP6D or SRP6R,is used as the only physically active compound in the treatment ofneuropathic pain without a second active agent, such as GABA analogous,such as Gabapentin (Neurontin).

In other embodiments, the compositions as described herein can beadministered to a subject concurrently with and/or in combination with asecond active ingredient, such as an opioid or an non-steroidalanti-inflammatory drug (NSAID). Opioid drugs work by binding to opioidreceptors in the brain and spinal cord. Non-limiting examples suchopioids comprise codeine, fentanyl, hydrocodone, hydrocodone/ApAP,hydromorphone, meperidine, methadone, morphine, oxycodone, oxycodone andApAP, oxycodone and naloxone, Nonsteroidal anti-inflammatory drugs(NSAIDs) block the COX enzymes and reduce prostaglandins throughout thebody. As a consequence, ongoing inflammation, pain, and fever arereduced. Non-limiting examples of NSAIDS comprise aspirin, celecoxib,diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, ketoprofen,ketorolac, nabumetone, naproxen, cixaprozin, piroxicam salsalate,sulindac, and tolmetin.

Compounds of as described herein, for example SRD6R and SRP6D, can beincorporated into pharmaceutical cot positions suitable foradministration. Such compositions can comprise a compound as describedherein and a pharmaceutically acceptable carrier. Thus, in someembodiments, the compounds of the invention are present in apharmaceutical composition.

For example, a pharmaceutical compositions comprising a compound asdescribed herein can be used for preventing, and/or treating pain, suchas a therapeutically effective amount of SRP6D and SRP6R in admixturewith a pharmaceutical acceptable carrier or excipient. For example, atherapeutically effective amount of SRP6D can be administered to asubject so as to prevent the onset of pain, or prevent the severity ofpain from increasing.

“Treatment” can refer to an approach for obtaining beneficial or desiredclinical results, for example improvement or alleviation of any aspectof pain, such as acute, chronic, inflammatory, neuropaihic. Orpost-surgical pain. Beneficial or desired clinical results comprise, butare not limited to, one or more of the following: in lessening severity,alleviation of one or more symptoms associated with pain including anyaspect of pain (such as shortening duration of pain, and/or reduction ofpain sensitivity or sensation).

“Ameliorating” pain or one or more symptoms of pain can refer to alessening or improvement of one or more symptoms of a pain as comparedto not administering a composition as described here, such as SRP6D andSRP6R. “Ameliorating” can also comprise shortening or reduction induration of a symptom. For example, a therapeutically effective amountof SRP6D or SRP6R can be administered to a subject afflicted with painso as to ameliorate, or lessening, the pain.

The term “alleviate” or “alleviating” can refer to lightening orlessening the severity of a symptom, condition, or disorder. Forexample, a treatment, such as SRP6D or SRP6R, that reduces the severityof pain in a subject can be said to alleviate pain. For example, atherapeutically effective amount of SRP6D can be administered to asubject afflicted with pain, wherein the severity of the pain islessened. It is understood that, in certain circumstances, a treatmentcan alleviate a symptom or condition without treating the underlyingdisorder. In certain aspects, this term can be synonymous with thelanguage “palliative treatment.”

Embodiments can be used for reducing the incidence of pain or delaying,non-limiting examples of which comprise post-surgical, neuropathic,dental, ophthalmic, arthritic, post- and/or traumatic pain. “Reducingincidence” of pain can refer to any of reducing severity (which caninclude reducing need for and/or amount of (e.g., exposure to) otherdrugs and/or therapies generally used for this conditions), duration,and or frequency (including, for example, delaying or increasing time topain in an individual). As is understood by those skilled in the art,individuals can vary in terms of their response to treatment, and, assuch, for example, a “method of reducing incidence of pain in anindividual” reflects administering compositions as described herein,such as SRP6D and SRP6R, based on a reasonable expectation that suchadministration can cause such a reduction in incidence in thatparticular individual.

“Delaying” the development of pain can refer to deterring, hindering,slowing, retarding, stabilizing, and/or postponing progression of pain.This delay can be of varying lengths of time, depending on the historyof the disease and/or individuals being treated. As is evident to oneskilled in the art, a sufficient or significant delay can, in effect,encompass prevention, in that the individual does not develop pain. Amethod that “delays” development of the symptom is a method that reducesprobability of developing the symptom in a given time frame and/orreduces extent of the symptoms in a given time frame, when compared tonot using the method.

“Development” or “progression” of pain can refer to initialmanifestations and/or ensuing progression of the disorder. Developmentof pain can be detectable and assessed using standard clinicaltechniques as well known in the art. However, development also refers toprogression that can be undetectable. For purpose of this invention,development or progression refers to the biological course of thesymptoms. “Development” includes occurrence, recurrence, and onset. Asused herein “onset” or “occurrence” of pain includes initial onset andor recurrence. For example, embodiments as described herein can be usedto prevent the development of pain, or prevent the progression of pain.

Embodiments can be used for palliating pain, non-limiting examples ofwhich comprise post-surgical, neuropathic, dental, ophthalmic,arthritic, post- and/or traumatic pain.

“Palliating” pain or one or more symptoms of pain can refer to lesseningthe extent of one or more undesirable clinical manifestations of pain inan individual or population of individuals treated with a composition asdescribed herein, such as SRP6D and SRP6R.

Embodiments comprise administering to a subject an effective amount of acomposition as described herein, such as SRP6D and SRP6R for thetreatment of pain.

An “effective amount”, “sufficient amount” or “therapeutically effectiveamount” can refer to an amount sufficient to effect beneficial ordesired clinical results including alleviation or reduction in the painsensation. For purposes of this invention, an effective amount of acomposition as described herein, such as SRP6D and SRP6R, can comprisean amount sufficient to treat, ameliorate, reduce the intensity of orprevent pain of any sort, including acute, chronic, inflammatory,neuropathic, or post-surgical pain. In some embodiments, an effectiveamount of compositions as described herein can modulate the sensitivitythreshold to external stimuli to a level comparable to that observed inhealthy subjects. In other embodiments, this level is not be comparableto that observed in healthy subjects, but is reduced compared to notreceiving the combination therapy.

Specific compositions as described herein, such as SRP6D and SRP6R, canbe administered to a subject by any suitable means, such as oral,intravenous, parenteral, subcutaneous, intrapulmonary topical,intravitreal, dermal, transmucosal, rectal, and intranasaladministration. Parenteral infusions include intramuscular, intravenous,intraarterial, or intraperitoneal administration. The compounds can alsobe administered transdermally, for example in the form of a slow-releasesubcutaneous implant or as a transdermal patch. They can also beadministered by inhalation. Although direct oral administration cancause some loss of desired activity, for example pain relievingactivity, the analgesics can be packaged in such a way to protect theactive ingredient(s) from digestion by use of enteric coatings, capsulesor other methods known in the art.

Controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. The use of an optimally designed controlled-releasepreparation in medical treatment is characterized by a minimum of drugsubstance being employed to cure or control the condition in a minimumamount of time. Advantages of controlled-release formulations includeextended activity of the drug, reduced dosage frequency, and increasedpatient compliance. In addition, controlled-release formulations can beused to affect the time of onset of action or other characteristics,such as blood levels of the drug, and can thus affect the occurrence ofside (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

Solutions or suspensions used for parenteral, intradermal, orsubcutaneous application can include, for example, the followingcomponents; a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; anti-inflammatory agents; antioxidants suchas ascorbic acid or sodium bisulfite; chelating agents such asethylenediaminetetraacetic acid; buffers such as acetates, citrates orphosphates and agents for the adjustment of tonicity such as sodiumchloride or dextrose. pH can he adjusted with acids or bases, such ashydrochloric acid or sodium hydroxide.

Compositions as described herein, such as SRP6D and SRP6R, can beadministered to the subject one time (e.g., as a single injection ordeposition). While the term for administering of at least one compoundto prevent pain varies depending on species, and the nature and severityof the condition to be prevented or treated, the compound can beadministered to humans for a short term or a long term, i.e. for 1 weekto 1 year. For example, administration can be once or twice daily to asubject in need thereof for a period of time, such as one week or onemonth.

The dosage can vary depending upon known factors such as thepharmacodynamic characteristics of the active ingredient and its modeand route of administration; time of administration of activeingredient; age. sex, health and weight of the recipient; nature andextent of symptoms; kind of concurrent treatment, frequency of treatmentand the effect desired; and rate of excretion.

A therapeutically effective dose can depend upon a number of factorsknown to those of ordinary skill in the art. The dose(s) can vary, forexample, depending upon the identity, size, and condition of the subjector sample being treated, further depending upon the route by which thecomposition is to be administered, if applicable, and the effect whichthe practitioner desires. These amounts can be readily determined by theskilled artisan.

In some embodiments, the therapeutically effective amount is at leastabout 0.1 mg/kg body weight, at least about 0.25 mg/kg body weight, atleast about 0.5 mg/kg body weight, at least about 0.75 mg/kg bodyweight, at least about 1 mg/kg body weight, at least about 2 mg/kg bodyweight, at least about 3 mg/kg body weight, at least about 4 mg/kg bodyweight, at least about 5 mg/kg body weight, at least about 6 mg/kg bodyweight, at least about 7 mg/kg body weight, at least about 8 mg/kg bodyweight, at least about 9 mg/kg body weight, at least about 10 mg/kg bodyweight, at least about 15 mg/kg body weight, at least about 20 mg/kgbody weight, at least about 25 mg/kg body weight, at least about 30mg/kg body weight, at least about 40 mg/kg body weight, at least about50 mg/kg body weight, at least about 75 mg/kg body weight, at leastabout 100 mg/kg body weight, at least about 200 mg/kg body weight, atleast about 250 mg/kg body weight, at least about 300 mg/kg body weight,at least about 3500 mg/kg body weight, at least about 400 mg/kg bodyweight, at least about 450 mg/kg body weight, at least about 500 mg/kgbody weight, at least about 550 mg/kg body weight, at least about 600mg/kg body weight, at least about 650 mg/kg body weight, at least about700 mg/kg body weight, at least about 750 mg/kg body weight, at leastabout 800 mg/kg body weight, at least about 900 mg/kg body weight, or atleast about 1000 mg/kg body weight.

A therapeutically effective dose can depend upon a number of factorsknown to those of ordinary skill in the art. The dose(s) can vary, forexample, depending upon the identity, size, and condition of the subjector sample being treated, further depending upon the route by which thecomposition is to be administered, if applicable, and the effect whichthe practitioner desires. These amounts can be readily determined by theskilled artisan.

In an embodiment, the recommended daily dose range of a compound asdescribed herein for pain as described herein lies within the range offrom about, a daily dose of about 1 mg/body to about 10 g/body, forexample about 5 mg/body to about 5 g/body, or for example about 10mg/body to about 2 g/body of the active ingredient is generally givenfor treating this disease, and an average single dose of about 0.5 mg toabout 1 mg, about 5 mg, about 10 mg, about 50 mg, about 100 mg, about250 mg, about 500 mg, about 1 g, about 2 g and about 3 g is generallyadministered. Daily dose for administration in humans for treating orameliorating pain could be in the range of about 1 mg/kg to about 300mg/kg.

A compound as described herein, for example SRP6D or SRP6R, orcomposition comprising the same can be administered to the subject onetime (e.g., as a single injection or deposition). Alternatively,administration can be once or twice daily to a subject in need thereoffor a period of from about 2 to about 28 days, or from about 7 to about10 days, or from about 7 to about 15 days. It can also be administeredonce or twice daily to a subject for a period of 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12 times per year, or a combination thereof.

Single unit dosage forms of the disclosure are suitable for oral,mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal),parenteral (e.g., subcutaneous, intravenous, bolus kiection,intramuscular, or intraanerial), topical (e.g., eye drops or otherophthalmic preparations), transdermal (e.g., cream, lotion, or dermalspray) or transcutaneous administration to a patient. Examples of dosageforms include, but are not limited to: tablets; caplets; capsules, suchas soft elastic gelatin capsules; cachets; troches; lozenges;dispersions; suppositories; powders; aerosols (e.g., nasal sprays orinhalers); gels; liquid dosage forms suitable for oral or mucosaladministration to a patient, including suspensions (e.g., aqueous ornon-aqueous liquid suspensions or solutions, oil-in-water emulsions, ora water-in-oil liquid emulsions), solutions, and elixirs, liquid dosageforms suitable for parenteral administration to a patient; eye drops orother ophthalmic preparations suitable for topical administration; andsterile solids (e.g., crystalline or amorphous solids) that can bereconstituted to provide liquid dosage forms for parenteraladministration to a subject.

The composition, shape, and type of dosage forms of the disclosure willtypically vary depending on their use. Further, the dosage can varydepending upon known factors such as the pharmacodynamic characteristicsof the active ingredient and its mode and route of administration; timeof administration of active ingredient; age, sex, health and weight ofthe recipient; nature and extent of symptoms; kind of concurrenttreatment, frequency of treatment and the effect desired; and rate ofexcretion.

For example, a dosage form used in the acute treatment of a disease cancontain larger amounts of one or more of the active agents it comprisesthan a dosage form used in the chronic treatment of the same disease.Similarly, a parenteral dosage form can contain smaller amounts of oneor more of the active agents it comprises than an oral dosage form usedto treat the same disease. These and other ways in which specific dosageforms encompassed by this disclosure will vary from one another will bereadily apparent to those skilled in the art, See, e.g., Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

Any of the therapeutic applications described herein can be applied toany subject in need of such therapy, including, for example, a mammalsuch as a mouse, a rat, a dog, a cat, a cow, a horse, a rabbit, amonkey, a pig, a sheep, a goal, or a human. In some embodiments, thesubject is a mouse, rat, pig, or human. In some embodiments, the subjectis a mouse. In some embodiments, the subject is a rat. In someembodiments, the subject is a pig. In some embodiments, the subject is ahuman.

Medical Kits

A “kit” or “medical kit” of the disclosure comprises a dosage form of acompound of the disclosure, such as SRP6D or SRP6R, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,prodrug, or clathrate thereof. A kit can also include both SRP6D andSRP6R, either in combination, such as in a single tablet, or providedseparately, such as in two tablets.

Kits can further comprise additional active agents, for example opioidsor non-steroidal anti-inflammatories, examples of which are describedherein. For example, an opioid can be provided in a kit described hereinat dose lower than that currently used by a subject so as to decreasetotal body opioid consumption and the deleterious effects associatedwith prolonged opioid use. Kits of the disclosure can further comprisedevices that are used to administer the active ingredients. Examples ofsuch devices include, but are not limited to, syringes, drip bags,patches, and inhalers. Kits can also comprise printed instructions foradministering the compound to a subject.

Kits of the invention can further comprise pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a seated container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:Water for Injection USP; aqueous vehicles such as, but not limited to,Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles such as, but not limited to, ethyl alcohol,polyethylene glycol and polypropylene glycol; and non-aqueous vehiclessuch as, but not limited to, corn oil, cottonseed oil peanut oil, sesameoil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

EXAMPLES

Examples are provided below to facilitate a more complete understandingof the invention. The following examples illustrate the exemplary modesof making and practicing the invention. However, the scope of theinvention is not limited to specific embodiments disclosed in theseExamples, which are for purposes of illustration only, since alternativemethods can be utilized to obtain similar results.

Example 1

Discovery of ApAP Analogs with Retained Analgesia and MinimalHepatotoxicity

Although ApAP is one of the most commonly used medicines worldwide,hepatotoxicity is the most significant risk, and overdose or use inpatients with compromised liver function is the most common cause offuliminant hepatic failure. Oxidation of ApAP the metaboliteN-acetyl-p-benzoquinone imine (NAPQI) is the likely mechanism for thehepatotoxicity. We previously synthesized an ApAP analogue bearing aheterocyclic moiety linked to the p-acylaminophenol fragment. Analogs tothe metabolite of this ApAP analog were synthesized (SRP 6D and R tofurther enhance the safety profile of these new chemical entities whileretaining analgesia. These novel compounds display analgesia comparableto ApAP with retained antipyresis in a mouse model, while exhibitingdecreased hepatotoxicity in human hepatocyies (hHEPs). Compared to ApAP,SRP 6D and R resulted in decreased lactate dehydrogenase and increasedreduced glutathione in hHEPs and demonstrated a favorable cytochromeP450 metabolism and marked decreased liver function tests in an in vivomouse model. Given the widespread use of ApAP as a standalone medicationand in various combination formulations, this pre-clinical dataestablishes a novel pipeline of compounds to develop that maintainanalgesia but have markedly diminished hepatotoxioity

Introduction

Acetaminophen, ApAP, also known as paracetamol, isN-acetyl-para-aminophenol (ApAP), the most common over the counteranalgesic used worldwide[2]. The chemical structures of ApAP,n-acetyl-p-aminophenol, and ApAP metabolite N-arachidonoylphenolamine(AM404), are below:

An analine analgesic, it was synthesized in the 1878 in search of asafer acetanilide derivative devoid of methemoglobinemia toxicitycausing cyanosis with analgesic and antipyretic activity, and brieflyintroduced into clinical practice in 1887[3]. However, it was not widelyadopted as an analgesic until the 1950s after Brodie and Axelroddemonstrated that ApAP was the major metabolite of the analines,acetaniside and phenacetin[4], devoid of methemoglobinemia andnephropathy, re-introducing ApAP.

Even though it has been used over several decades, ApAP has a rathernarrow therapeutic index and significant side effects are associatedwhen overdose occurs, primarily hepatotoxicity. Hepatotoxicity has beenthe major caveat with use of ApAP, primarily due to accidental orintentional overdose being the most common cause of fulminant hepaticfailure in the United States[5] and in the Western world[2], requiringaggressive intensive care support and, in rare cases, livertransplantation[6]. Cases of ApAP hepatotoxicity can also occur inpatients with compromised liver function not ingesting large doses ofApAP. Hepatotoxicity occurs via is oxidation of ApAP to thecorresponding N-acetyl-p-benzoquinone imine (NAPQI)[2, 7] thrucytochrome P450 metabolism, with resultant glutathione depletion,mitochondrial dysfunction and oxidative stress.

Despite this long history, ApAP mechanism of action is still unclear,and this has been a challenge towards designing safer analgesic andantipyretic analogs. Distinct from non-steroidal anti-inflammatory drugs(NSAIDs), which principally have anti-inflammatory and only moderateanalgesia and anti-pyretic effects through inhibition of cyclooxygenases(COX-1, -2), whether or not ApAP is a COX inhibitor has been debated asit has no appreciable clinical anti-inflammatory functions. Some suggestit possesses the ability to act as a COX-inhibitor by reducing theprotoporphyrin radical cation in the peroxidase site of prostaglandin H2synthases (COX-enzymes)[8], thereby reducing the prostaglandinsresponsible for pyrexia[9].

The discovery in 2005 of the ApAP metabolite N-arachidonoylphenolamine(AM404, FIG. 1) as the amide formed from 4-aminophenol and arachidonicacid by fatty amide hydrolase in the brain and spinal cord[10] suggestthat ApAP can exert its effects thru activation of the capsaicinreceptor/TRPV1 (transient receptor potential cation channel, subfamilyV, member 1)[11] and/or the cannabinoid CB1 receptor system[12]. Theseputative mechanisms of action have led to the development of ApAPanalogs, including an adamantyl analog of ApAP[13] that targets theTRPA1 ion channel (transient receptor potential cation channel subfamilyA member 1). Another strategy employed has been to target thecannabinoid receptors CB1 and CB2 thru modification of the mainmetabolite of ApAP, AM404, by placing an anandamide chain instead of theacetamido group[14].

We have taken another approach, creation of novel ApAP analogs that arenot metabolized to NAPQI and, hence, result in minimal hepatotoxicity.This was achieved by replacing the methyl group with saccharin andvarious derivatives and analogs thereof, creating2-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)-N-(4-hydroxyphe-nyl)alkanecarboxamides, bearing a heterocyclic moiety linked to thep-acylaminophenol fragment (SCP-1)[15]. This modification also improvesconsiderably its water solubility and maintains analgesia[16]. Here wedescribe the synthesis of novel analgesics,2-<[(4-Hydroxy-phenylcarbamoyl)-methyl]-sulfamoyl>-n,n-diethyl-benzamide(SRP-6D) andn-[2-(2,3-Dihydroxyphenyl)-ethyl-2-<[(4-hydroxy-phenylcarbamoyl)-methyl]-sulfamoyl>-benzamide(SRP-6R, FIG. 1), which are analogs to the metabolite of SCP-1 (SCP-1M)that display analgesia, a favorable cytP450 metabolism profile andminimal hepatotoxicity.

Methods

Synthesis of Saccharin Derivatives

Preparation of Starting Material 5 and Saccharin Derivatives 7

2-Chloro-N-(4-hydroxyphenyl)acetamide 3 was synthesized by acylation of4-antinophenol 1 with 2-chloroacetic anhydride, using a heterogeneoussilica gel supported NaHSO₄ catalyst (NaHSO₄.SiO₂) in CH₂Cl₂ at roomtemperature. Compound 3 was obtained in 75% yield (Scheme 1).

Preparation of compound 5 was carried out by using the proceduredescribed by Trudell et al[17]. Thus, 2-chloro-N-(4-hydroxy-phenyl)acetamide 3 and saccharin sodium salt 4 were heated to reflux in DMFwith catalytic amount of NaI. The saccharin derivate 5 was obtained byprecipitation in ice/water and crystallized in ethanol/water, to givecompound 5 (Scheme 1).

Reaction between compound 5 and amines 6 produces the opening of thesaccharin heterocyclic ring to give the desired N-substituted amides(Scheme 2). These reactions are carried out mostly in aqueous solutionuntil complete disappearance of 5 by TLC.

Preparation of Saccharin Derivatives

NaHSO₄.SiO₂ catalyst. To a solution of 4.14 g (0.03 mol) of NaHSO₄.H₂Oin 20 mL of water was added 10 g of silica gel (column chromatographicgrade, 60 Å, 200-400 mesh). The mixture was stirred for 15 min at roomtemperature and then gently heated in the rotary evaporator, until afree-flowing white solid was obtained. The catalyst was further driedunder vacuum for at least 48 h prior to use.

2-Chloro-N-(4-hydroxyphenyl)acetamide, 3. To a mixture of 4-aminophenol1 (436 g, 40 mmol) and 2-chloroacetic anhydride 2 (8.2 g, 48 mmol) inCH₂Cl₂ (200 mL) NaHSO₄.SiCO₂ (4 g) was added. The mixture was heated to35° C. for 2.5 h and the reaction was monitored by TLC. The precipitatewas dissolved in ethanol and the mixture was filtered. The filtrate wasconcentrated and the residue washed with water, to give 3 (5.74 g, 75%)as a white solid: mp 142-144° C.; ¹H NMR (300 MHz DMSO-d₆) δ 4.18 (s,2H, CH₂), 6.71 (d, 2H, J=8.9 Hz, H-1,5), 7.36 (d, 2H, J=8.9 Hz, H-2,4),9.27 (s, 1H, OH), 10.03 (s, 1H. NH) ppm.

¹³C NMR (75 MHz DMSO-d₆) δ 44.0, 115.6, 121.6, 130.5, 154.2, 164.3. ppm.

2-(1,1-Dioxo-1,2-dihydrobenzo[d]isothiazol-3-one-2-yl)-N(4-hydroyphenyl)acetamide, 5. 2-Chloro-N-(4-hydroxyphenyl)acetamide 3 (5 g, 27 mmol) andsaccharin sodium monohydrate 4 (7.25 g, 32.4 mmol) salt were mixedtogether in the presence of NaI (0.015 g, 2.30 mmol) in DMF (15 mL). Themixture was heated to reflux (160° C.) for 2 h, cooled to 25° C., andpoured into cold water until no additional precipitate formed todisplace the DMF. The sticky white precipitate was collected by vacuumfiltration and allowed to dry in air for 90 min. The filter cake wasdissolved in 50% ethanol-water and crystallized to furnish 6.72 g of 5as white crystals 75% yield: mp 204-207° C.; ¹H NMR (300 MHz DMSO-d₆) δ4.52 (s, 2H, CH₂), 6.71 (d, 2H, J=8.5 Hz, H-1,5), 7.34 (d, 2H, J=8.5 Hz,H-2,4), 8.05 (m, 2H, 2H-arom), 8.15 (d, 1H, J=7.1, H-atom), 8.35 (d, 1H,J=7.4, H-arom), 9.26 (s, 1H, OH), 10.06 (s, 1H, NH) ppm.

¹³C NMR (75 MHz DMSO-d₆) δ 40.6, 115.2, 121.0, 121.8, 125.2, 126.5,130.1, 135.5, 135.9, 136.0, 153.7, 158.8, 162.6 ppm.

2-<[(4-Hydroxy-phenylcarbamoyl)-methyl]-sulfamoyl>-N-methyl-benzamide(7a). OSA-6c

To methylamine aqueous solution (10 mL, 40% 119 mmoL) compound 5 (0.6 g,1.8 mmol) was added. The mixture was stirred for 35 min and dried undervacuum to give a white solid. This compound was purified by flash columnchromatography (Ethyl acetate/Hexane 9:1) to give 0.59 g, 89%: mp 93-95°C. ¹H NMR (300 MHz, DMSO-d₆) δ, 2.80 (d, 3H, J=4.5 Hz, CH3), 3.67 (s,2H, CH2), 6.64 (d, 2H, J=8.8 Hz, H-1,5), 7.20 (d, 2H, J=8.8 Hz, H-2,4),7.49 (s, 1H, NH), 7.55 (d, 1H, J=7.2 Hz, H-arom), 7.65 (m, 2H, H-arom),7.86 (d, 1H, J=7.4 Hz, H-arom), 8.69 (s, 1H, J=4.5 Hz, NH), 9.20 (s, 1H,NH), 9.76 (s, 1H, OH) ppm. ¹³C NMR (75 MHz, DMSO) δ 26.7, 39.1, 39.4,39.7, 39.9, 40.2, 40.5, 40.8, 46.3, 115.4, 129.0, 121.4, 129.6, 130.3,130.4, 133.2, 136.2, 137.2, 153.9, 165.8, 169.2 ppm.

2-<[(4-Hydroxy-phenylcarbamoyl)-methyl]-sulfamoyl>-N,N-diethyl-benzamide(7b). OSA-6d

To a solution of diethylamine (0.657 g, 0.93 mL, 9 mmol) in water (15mL) compound 5 (1 g, 3 mmol) was added. The mixture was stirred for 2 hat room temperature. The obtained solid was dried under vacuum and waspurified by flash column chromatography (Ethyl acetate/EtOH 6:4) tosupply a white solid (0.960 g, 76%): mp 187-189° C.; ¹H NMR (300 MHz,DMSO) δ 1.19 (t, J=7.2 Hz, 6H, 2CH₃), 2.93 (q, J=7.2 Hz, 4H, 2CH₂), 3.55(s, 2H, CH₂), 6.63 (d, J=8.7 Hz, 2H, H-arom), 7.23 (d, J=8.7 Hz, 2H,H-arom), 7.40 (t, J=7.2 Hz, 1H), 7.52 (t, J=7.1 Hz, 1H, H-arom), 7.60(d, J=7.2 Hz, 1H, H-arom), 7.73 (d, J=7.5 Hz, 1H, H-arom), 8.93 (bs, 1H,NH), 9.20 (bs, 1H, NH), 9.99 (s, 1H, OH) ppm. ¹³C NMR (75 MHz, DMSO) δ11.1, 41.3, 46.4, 114.8, 120.8, 127.1, 127.2, 129.9, 130.0, 132.0,135.3, 141.6, 153.2, 165.4 ppm.

2-<[(4-Hydroxy-phenycarbamoyl)-methyl]-sulfamoyl>-N-(2-pyrrolidin-1-yl-ethyl)-benzamide(7c). OSA-6u

To a solution of 1-(2-animoethyl)pyrrolidine (0.084 g, 0.76 mL, 6 mmol)in acetonitrile (15 mL) compound 5 (0.941 g, 2.8 mmol) was added. Themixture was stirred for 1 h at room temperature. The obtained solid wasfiltrated and purified by flash column chromatography (Ethylacetate/EtOH 9:1) to supply a while solid (1.1 g, 80%): mp 141-142° C.;¹H NMR (300 MHz, DMSO) δ 1.71 (s, 4H), 2.54 (s, 4H), 2.64 (s, 2H), 3.43(s, 2H), 3.85 (s, 2H), 6.59 (d, J=7.8 Hz, 2H), 6.95 (d, J=7.7 Hz, 2H),7.44 (dd, J=7.4 Hz, 2H), 7.56 (t, J=7.5 Hz, 1H), 7.80 (d, J=7.7 Hz, 1H),9.21 (s, 1H), 8.81 (s, 1H), 9.87 (s, 1H) ppm. ¹³C NMR (75 MHz, DMSO) δ23.6, 38.2, 46.0, 53.4, 54.5, 115.7, 122.2, 129.5, 129.8, 133.2, 137.2,137.5, 154.5, 166.9, 167.8 ppm.

N-[2-(2,3-Dihydroxypheoyl)-ethyl-2-<[(4-hydroxy-phenylcarbamoyl)-methyl]-sulfamoyl>-benzamide(7d), OSA-6r

Dopamine hydrochloride (0.381 g, 2 mmol), Na₂CO₃ (0.215 g, 2 mmol) andcompound 5 (0.333 g 1 mmol) were added to 10 ml of EtOH and heated to65° C. The mixture was stirred for 18 h. The obtained solid wasfiltrated and purified by flash column chromatography (Ethylacetate/EtOH 9:1) furnished compound 7d (0.350 g, 71%): mp 87-89° C.;

¹H NMR (300 MHz, DMSO) δ 2.68 (t, J=7.4 Hz, 2H, CH₂), 3.40 (t, J=6.8 Hz,2H, CH₂), 3.68 (d, J=5.8 Hz, 2H, CH₂), 6.50 (dd, J=8.0, 1.5 Hz, 1H,H-arom), 6.70-6.58 (m, 4H), 7.21 (d, J=8.7 Hz, 2H, H-arom), 7.50-7.39(m, 2H, H-arom, NH), 7.63 (dq, J=7.5, 6.8 Hz, 2H, H-arom), 7.87 (dd,J=7.3, 1.0 Hz, 1H, H-arom), 8.65 (s, 1H, OH), 8.77 (s, 1H, OH), 8.82 (t,J=5.6 Hz, 1H, NH), 9.18 (s, 1H, NH), 9.75 (s, 1H, OH) ppm. ¹³C NMR (75MHz, DMSO) δ35.0, 42.1, 46.7, 115.7, 116.2, 116.7, 120.0, 121.6, 129.2,129.8, 130.5, 130.6, 130.7, 133.4, 136.4, 137.4, 144.2, 145.7, 154.1,165.9, 168.8 ppm.

Additional analogs of the above-described novel compounds were similarlyformed via reaction of compound 5 with various reagents throughprocesses similar to those described above with respect to selectanalogs of the herein-described novel analgesics. In certainembodiments, compound 5 was mixed with a desired reagent in a solutionof water, ethanol, methanol, acetonitrile, tetrahydrofuran, aqueousmethylamine, or any other organic or inorganic solvents known in the artas appropriate.

Potential reagents include NH₃, NH(CH₃)₂, NH₂CH3, NH(CH₂CH₃)₂,N₂(CH₂)₄HCH₂C₆H₅, NH₂CH₂C₆H₅, NHO(CH₂)₄, NH₂CH₂CH₂CH₂CH₃, NH₂CH₂C₆H₄CH₃,NH₂CH₂C₆H₃Cl₂, NH₂CH₂C₆H₅CH₃, NH₂CH₂C₆H₅Cl, NH₂CH₂C₆H₅NO₂, NH₂C₅H₄,NH₂CH₂C(CH₃)₂, NH₂C(CH₃)₂, NH₂CH₂CH₂C₆H₃(OH)₂, NH₂CH₂C₆H₄N,NH₂CH₂C₆H3NCH₃, NH₂CH₂CH₂C₄H₄N, NH(CH₃)CH₂CH₂OH, NH₂CH₂CH(OH)CH₂NH₂; orpharmaceutically acceptable salts thereof.

Analogs created according to methods of synthesis described hereininclude compositions having the following chemical formulas.

Analgesia Assays

Two different assays were utilized to quantify the analgesic effects ofthe compounds. All tests were performed on CD1 male mice. CompoundsSCP-1, SCP-1M and SRP-6D, R (South Rampart Pharmaceuticals. New Orleans,La.), or APAP (Sigma, St. Louis, Mo.) and administered in aconcentration of 75 mg/kg after suspension in the vehicle (0.9% saline).In some embodiments, the vehicle can comprise Agent K, 0.2%, Bio-serve,or Labrafil 1944 (Gottefosee, France). Compound or vehicle wasadministered orally by lavage under brief halothane anesthesia toanimals fasted overnight.

Acetic acid-induced abdominal writhing assay. Contraction of theabdominal muscle and stretching of the hind limbs is induced as aresponse to intraperitoneal (ip) injection of an acetic acid solution,as described Hendershot and Forsaith, 1959. In this model of visceralpain, abdominal contractions (writhing) is induced in mice by an ipinjection of 0.4% acetic acid at a dose of 10 mL/Kg, 25 min after drugadministration. The number of writhes is counted for 10 min beginning 5min after acetic acid injection. All animals (CD1 male mice) were fastedovernight (15 hours) prior to testing and the compounds wereadministered orally to animals belonging to the treatment groups, ApAPand SRP compounds at 75 mg/kg body weight). Data is expressed asmean±SEM, n=7.

Tail-flick assay. Analgesic effect of drugs was determined by using thereaction time (latency) of mice to thermal stimulation of the tail tip.All animals (CD1 male mice) were fasted overnight (15 hours) and, theirbaseline tail flick latency (seconds) was recorded using an IITC TailFlick Analgesia Meter. The tail of each mouse was exposed to a focusedbeam of light and the latency to remove the tail from the path of thestimulus were recorded electronically using a photoelectric cell of theIITC Tail Flick Analgesia Meter. The stimulus intensity was adjusted toproduce baseline latencies of 3-6 seconds. After measurement of baselinelatency, drugs were administered per os to animals belonging to thetreatment groups—(ApAP and SRP compounds at 600 mg/Kg body weight);control group received vehicle (0.9% saline only). At 30 minutes postinjection, tail flick latency was recorded again to determine totalchange in latency. Percentage of maximum analgesia for each mouse werecalculated with the formula. Percentage Analgesia=100*}[(Latency to tailflick after drug injection)−(Latency to tail flick at baseline)]/[(12sec cutoff time)−(Baseline latency)]}. Data expressed as mean±SEM, n=10.

Antipyresis

The antipyretic effect of the compounds was assessed utilizing bakeryeast-induced hyperthermia. All animals (CD1 male mice) were fastedovernight (15 hours) and, their baseline temperature was recorded usinga Cole-Palmer rectal thermometer probe. Then they were injected thru theip route with a pyrogenic dose of baker yeast (15% yeast, 0.1 ml/10 gbody weight) while, control and vehicle group received an ip injectionof vehicle (0.9% saline). Temperatures were again recorded at 4 hours,after which, the compounds were administered orally to febrile animalsbelonging to the treatment groups—(ApAP and SRP compounds at 300 mg/Kgbody weight). Two hours post-injection, rectal temperatures wererecorded once again, to determine total change in body temperature.Percentage Change in body temperature is calculated with the formula.Percentage Change=[(Total change in body temperature)/(Basetemperature)*100]. Data is expressed as mean±SEM, n=10.

Cells/Cell Lines

Hepatocyte cell line (HEPG-2 cells) and primary human hepatocyles(hHEP). HepaRG cells procured from Thermo Fisher Scientific (Invitrogen)are terminally differentiated hepatic cells, which are derived from ahepatic progenitor cell line that retains many characteristics ofprimary human hepatocytes. HepaRG cells were grown and maintained inEMEM containing NEAA (non-essential amino acids), supplemented with 10%fetal bovine serum (FBS), and incubated at 37° C./5% CO2. hHEP,purchased from SCKISUI Xenotech, were obtained from a 61 year-oldCaucasian male individual donor who was a non-alcoholic and non-smoker.hHEP were grown in HCM (Clonetics, Walkersville, Md.), and maintained inHMM (Clonetics, Walkersville, Md.) at 37° C./5% CO2. Cultures (80%confluent) of HepaRG cells and hHEP growing in 6- and 24-well plates,respectively, were held 6-8 h in serum-free medium (EMEM, 0.5% FBS forHEPG-2, and HMM for primary hepatocytes) before the addition ofanalgesics. The serum-starved cells were treated with APAP, SRP-6D, R,SCP-1, SCP-1M or vehicle control for 6-8 h at 37° C.

Hepatotoxicity Testing for ApAP (APAP) Mediated Liver Injury (AIL1) inHepatocytes.

LDH assay. Using the Pierce LDH Cytotoxicity assay kit from ThermoScientific, cells were incubated in presence of various drug compounds,followed by collection of the medium supernatant. Release of LDH wasmeasured in 96 well plate formats. The absorbance was measured at 490 nmand 680 nm and the final result was absorbance observed at 680 nmsubtracted from absorbance observed at 490 nm (A_(490 nm)−A_(680 nm)).GSH assay. Using the ThiolTracker Violet Glutathione Detection reagentfrom Molecular Probes (Invitrogen), after hepatocytes were incubated inthe presence of various compounds, incubation medium was removed, cellsrinsed with D-PBS conditioned medium followed by incubation withpre-warmed ThiolTracker Violet dye (working solution prepared as permanufacturer's instructions) for 30 minutes. Fluorescence was measuredat the following wavelengths: excitation (404 nm) and emission (526 nm).The finalized result was expressed as relative fluorescence units (RFU),which indicates the cellular level of reduced glutathione (GSH) inintact cells.

Liver function assays. Alanine aminotransferase (ALT), aspartateaminotransferase (AST) and alkaline phosphatase (ALP) were run afterdosing CD1 male mice with 600 mg/Kg of compounds—ApAP and SRP D and Rorally, via gavage. The assays were run with serum collected from miceinjected with compounds or vehicle, after overnight (15 hours) fasting.After drug administration, water and food were provided to the mice adlibitum.

Cytochrome P450 Enzyme Metabolism Profile

The VIVIDCYP450 screening assay kit (Life Technologies.Invitrogen/Thermo Fisher Scientific) was used as an in vitro highthroughput screening. Here, each compound was mixed with a masterpre-mix comprising of CYP450 BACULOSOMES (which are microsomes preparedfrom insect cells expressing a specific human P450 isoenzyme), reagentand regeneration system, which contained glucose-6-phosphate andglucose-6-phosphate dehydrogenase. The mixture was pre-incubated at roomtemperature for 20 minutes. Following this, each CYP enzyme specificsubstrate and NADP were added and the mixture incubated at roomtemperature for 30 minutes. The reaction was stopped by addition of 0.5M Tris base. CYP activity was evaluated by measuring the fluorescence ofthe fluorescent metabolite generated from each CYP enzyme specificsubstrate.

Statistics. Changes of the withdrawal thresholds or latencies induced bya drug were first analyzed with a one-way ANOVA. Comparisons between theeffects of different drugs were then subjected to t-tests for unpairedmeans. A value of p<0.05 was considered significant.

Determination of metabolites: Gas chromatography was used to detectNAPQI (FIG. 11). Without being bound by theory, ApAP's toxicity ismediated via a toxic metabolite, N-acetyl-benzoquinoneimine (NAPQI),which depletes hepatic and renal glutathione, a cytoprolectiveendogenous metabolite. Gas chromatography demonstrates markedly lowerlevels of metabolism to NAPQI for select SRP compounds, compared toApAP, explaining the decreased hepatotoxicity.

Two-month-old CD-1 mice were fasted overnight. Next morning, followinglight halothane anesthesia, they were given po 5a, 3 mmol/kg in Tween 20(vehicle). They were placed in Nalgene metabolic cages (two mice percage) with water ad libitum. Food was supplied 6 h post dose treatment.The urine was collected in a plastic container, which was maintained inice during the 24-h collecting period. It was stored at 20° C. untiluse. At the time of the HPLC injection, aliquots were centrifuged in amicrofuge at 6000 rpm, 15° C. for 10 min, filtered with nylon filters(0.45 μm), and used immediately or lyophilized.

In the HPLC-MS analysis, a volume of 20 IL was injected. Whenlyophilized samples were used, they were dissolved in a mixture ofacetonitrile-0.1% ammonium acetate solution, pH 7 (50:50, v/v). TheHPLC-MS analyses were performed in an Agilent 1100 apparatus. Theanalytical column was a Luna 150 4.6 mm, C18 (5 lm) Phenomenex column.The mobile phase was de-gassed automatically by the electronic degassersystem. Before the analysis, the column was equilibrated and a gradientprogram was used for analysis of samples. The flow rate was maintainedat 1.5 mL/min and the column was maintained at 45° C.

Results

Compound molecular weight and the calculated Log P (cLog P). Low Clog Pvalues signify products with shorter half-lives, but higher cLog Pvalues indicate potential difficulties with compound absorption. Hence,intermediate values around 2 are likely desirable, particularly forcompounds to cross the blood-brain barrier.

TABLE 2 Compound Molecular weight (g/mol) Clog P ApAP 151.16  0.416 SCP1332.33 1.28 SCPM 350.35 From 1.07 to −2.48 SRP6D 405.47 1.42 SRP6R485.51 1.89

A total of 21 compounds were synthesized in our project to discovernovel chemical analogs to the metabolite of a heterocyclic moiety linkedto the p-acylaminophenol fragment of ApAP but we focus on two (SRP 6Dand R) that displayed analgesia comparable to ApAP, minimalhepatotoxicity, antipyresis, and a favorable cytochrome P450 metabolism.Analysis of the 21 compounds that were synthesized revealed some withlow cLogP values, ˜0.5, signifying likely poor bioavailability when usedas oral drugs. However, SRP6D (Clog P: 1.42) and SRP6R (Clog P: 1.89)are comparable to ApAP (Clog P 0.91) and SCP-1 (Clog P 1.28), Table.Note that SCP-1M has an interval Clog P that ranges from 1.07 to −2.48depending on medium pH because it has a polar ionizable group.

In two different in vivo analgesia mouse models, acetic acid-inducedabdominal writhing and the tail flick assays, SRP6D and R are comparableto ApAP (FIG. 1). The number of writhes induced by injection of aceticacid was 15.7+/−1.2 (n=3) for SRP6D (n=7, p<0.02) and 9.5+/−4, for SRP6R(n=7, p<0.008; FIG. 1 A), compared to 42.3+/−7.2 for vehicle only. Asecond set of experiments with n=7 demonstrates the analgesia of thevarious SRP compounds, which are similar to ApAP but lower than control(raw data for FIG. 1A);

TABLE 3 Analgesic activities of SRP compounds compared with ApAP asassessed by Acetic acid induced abdominal stretch (writhes) assay. No.of writhes counted within a 10 min time interval, Treatment 25 min postdrug administration, Groups beginning 5 min after acetic acid injectionControl 42 41 31 30 29 25 24 ApAP 11 12 14 15 16 16 16 SRP6D 15 11 14 2015 15 18 SRP6I 7 12 16 17 22 27 33 SRP6J 10 14 16 17 18 18 19 SRP6O 1114 16 17 17 18 24 SRP6P 14 17 24 26 29 30 14 SRP6R 9 12 18 20 25 26 26Note: n = 7 for all treatment group; animals belonging to control groupreceived 0.9% saline (vehicle) in lieu of drugs. Drugs of choice wereadministered per os (p.o.), at a dose of 75 mg/Kg body weight.

The tail flick test demonstrated a comparable significant analgesia forSRP6D, R to ApAP and marked improved latency compared to vehicle only(FIG. 1B).

SRP6D and SRP6R retain an antipyretic effect comparable to ApAP (FIG.4). Antipyresis was determined using two different mouse assays.Temperature curves demonstrate comparable antipyresis to ApAP for SRP6Dand SRP6R in an LPS-induced fever mouse model (FIG. 4A, B). Note that at2 h, 8 h and 10 h, the antipyresis is similar for ApAP, SRP6D and SRP6R.A Baker's yeast-induced fever model of antipyresis demonstrated similarantipyretic effects of ApAP and SRP6D and SRP6R (FIG. 4C, D). Comparableeffect of antipyretics on baker yeast-induced hyperthermia is noted inFIG. 4E for ApAP and SRP6D and SRP6R.

Next, the hepatotoxicity profile for compounds SRP6D and R, compared toApAP and to the first generation saccharin ApAP derivatives, SCP-1 andSCP-1M, was determined in both HepaRG and hHEPs. Decreased toxicity wasnoted for SRP6D and R, compared to ApAP: lactate dehydrogenase (LDH)release was consistently deceased and the amount of reduced glutathione(GSH) was increased for SRP6D and R, whereas ApAP led to an increasedLDH release (FIG. 3) and depletion of GSH (FIG. 2) in a time anddose-dependent manner. In mouse liver and human hepatocytes (HepaRG andhHEP), at human equivalent therapeutic doses, a dose- and time-dependenteffect of decreased hepatotoxicity thru decreased LDH and increased GSHrelease was observed with progressive clinical signs of liver injury forSRP6D and R but not ApAP. A marked reduction in liver function tests wasnoted for the SRP6D and R, compared to ApAP, the largest being in ALT.Increased levels of ALT, AST and AP enzyme activity for APAP was notedwhile SRP6D and R were similar to the control (vehicle only, FIG. 3C).

Lastly, a favorable cytochrome P450 metabolism for SRP6D and SRP6R wasnoted in various cytochrome P450 isoenzymes, including CYP3A4, CYP2D6,and CYP2E1. SRP6D and SRP6R only inhibit the activity of CYP2E1 andCYP3A4 by ˜25% compared to 50% for ApAP and have a marginal inhibitoryeffect for CYP2D6 (FIG. 5).

Discussion

We demonstrate minimal hepatotoxicity in two novel compounds that areanalogs to the metabolite of a saccharin derivative of ApAP. Using twowell-accepted hepatic cells[18] hHEPs and HepaRGs as cell-based in vitrohepatic models, a consistent reduction in LDH release and increasedreduced glutathione (GSH) release. These cells have the highestpredictive capacity for ApAP-induced acute liver failure[19]. Reducedhepatotoxicity was further corroborated in an in vivo model. As ApAPhepatotoxicity mechanisms are similar in both humans and mice[20], wethen chose the mouse to study clinical signs of liver injury (LFTs).

The in vitro toxicity assays utilized hHEPs and HepaRGs because they arethe more reproducible for toxicology studies. Despite the inherentlimits of primary cell cultures, including limited availability and ashort life-span. hHEPs are the best cells available for in vitrohepatotoxicity assays[21]. There are intrinsic difficulties with aprimary cell culture, however, and a recent toxigenomics analysis foundthat HepaRGs, a human hepatic cell line derived from hepatocellularcarcinoma, expresses liver-specific genes at similar levels of hHEPs[19]and displays the best adult hepatocyte-like phenotype out of allavailable hepatic cell lines[18].

Though widely used as an over the counter analgesic worldwide, the maindrawback of ApAP is its dose-dependent hepatotoxicity, which therapeuticindex is further narrowed in individuals with compromised hepaticreserve. However, cases of unintentional or intentional overdosing cannot be recognized in this short time period and ApAP remains the mostcommon cause of acute fulminant hepatic failure in the United States[5],usually after advertent ingestion of large quantities or by consumptionof over 3-4 grams per day in patients with impaired liver function, ApAPis available as a single-ingredient over the counter (OTC) medicine andin combination with other OTC medicines, including decongestants, and asprescription ApAP-opioid formulations: ApAP causing ALF likely occurs inunintentional cases when individuals ingest ApAP without knowledge ofApAP being present in these various formulations. In the United Statesaround 30,000 patients are admitted to hospitals every year for thetreatment of ApAP hepatotoxicity[22]. Although most patients experienceonly mild morbidity, such as hepatitis, cholestasis and a transientincrease in liver transaminases, acute liver failure ensues in untreatedpatients ingesting large doses and can progress to convulsions, coma anddeath if not promptly recognized and treated. N-acetylcysteine (NAC) canprevent ApAP-hepatic injury by providing cysteine to restore GSH ifgiven within 12 hours of ApAP overdose ingestion.

Another application of this technology could be to help curb the largeopioid epidemic in the United States. In 2016, drug overdose deathspeaked at >65,000 cases, mostly due to opioid pain relievers and heroin.Workplace injuries can be driving many of these cases because there isevidence that prescribed oral narcotics are the likely source and two ofthe largest concentrations of overdose deaths are in Appalachia and theSouthwest United States (CDC 2016).

NAPQI. APAP-induced hepatotoxicity is related to the formation of anelectrophilic reactive metabolite, NAPQI, which is detoxified throughconjugation with reduced glutathione (GSH). GSH is an important cellularantioxidant in the liver and GSH depletion is likely an important eventin APAP-induced acute liver injury, although this mechanism is stillpoorly understood[23], ApAP is metabolized by CYP enzymes, mainly CYP2E1and CYP3A, to NAPQI. However, following a toxic dose, GSH depletion isfollowed by formation of reactive oxygen and nitrogen species leading tomitochondrial permeability and hepatocyte death[24]. Without being boundby theory, a mechanism by which these compounds are minimallyhepatotoxic can be because they do not generate NAPQI.

References in this Example

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EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific substances and procedures described herein. Such equivalentsare considered to be within the scope of this invention, and are coveredby the following claims.

What is claimed:
 1. An analgesic compound of formula (I):

wherein R comprises NH₂, N(CH₃)₂, NHCH₃, N(CH₂CH₃)₂, N₂(CH₂)₄CH₂C₆H₅,NH(CH₂)₂C₆H₅, NHCH₂C₆H₅, NO(CH₂)₄, NHCH₂CH₂CH₂CH₃, NHCH₂C₆H₄CH₃,NHCH₂C₆H₃Cl₂, NHCH₂C₆H₅CH₃, NHCH₂C₆H₅Cl, NHCH₂C₆H₅NO₂, NHC₅H₄,NHCH₂C(CH₃)₂, NHC(CH₃)₂, NHCH₂CH₂C₆H₃(OH)₂, NHCH₂C₆H₄N, NHCH₂C₆H3NCH₃,NHCH₂CH₂C₄H₄N, N(CH₃)CH₂CH₂OH, NHCH₂CH(OH)CH₂NH₂; or a pharmaceuticallyacceptable salt thereof.
 2. The analgesic compound of claim 1, whereinsaid compound comprises formula (II):

wherein R¹ is H, OH, an alkyl group, a haloalkyl group, a halobenzylgroup, a phenyl group, —O-(alkyl), —O-(haloalkyl), —O-(halobenzyl),—O-(phenyl), an alkyl phenyl, a haloalkyl-phenyl, an alkyl-halobenzene,an alkyl-nitrobenzene, —O-(alkyl phenyl), —O-(haloalkyl)-phenyl, acycloalkane group, and wherein R² is selected from the group consistingof H and an alkyl group or a pharmaceutically acceptable salt thereof.3. The analgesic compound of claim 2, wherein R¹ comprises H, CH₃,(C₂)₂C₆H₅, CH₂C₆H₅, CH₂CH₂C H₂CH₃, CH₂C₆H₃Cl₂, CH₂C₆H₅CH₃, CH₂C₆H₅Cl,CH₂C₆H₅NO₂, C₅H₄, CH₂C(CH₃)₂, C(CH₃)₂, CH₂CH₂C₆H₃(OH)₂, CH₂C₆H₄N,CH₂C₆H₃NCH₃, CH₂CH₂C₄H₄N, CH₂CH₂OH, or CH₂CH(OH)CH₂NH₂; and wherein R²is selected from the group consisting of H and CH₃, or apharmaceutically acceptable salt thereof.
 4. The analgesic compound ofclaim 2, wherein alkyl comprises C_(N)H_(2N-1).
 5. The analgesiccompound of claim 4, wherein _(N) is 1-10.
 6. The analgesic compound ofclaim 1, 2 or 3, having the following chemical structure:


7. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


8. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


9. The analgesic compound, of claim 1, 2 or 3, having the followingchemical structure:


10. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


11. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


12. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


13. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


14. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


15. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


16. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


17. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


18. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


19. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


20. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


21. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


22. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


23. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


24. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


25. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


26. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


27. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


28. The analgesic compound of claim 1, 2 or 3, having the followingchemical structure:


29. The analgesic compound of claim 1, 2 or 3, wherein said compound hasa reduced risk of hepatotoxicity when administered in vivo.
 30. Theanalgesic compound of claim 1, 2 or 3, wherein said compound exhibitsanalgesia comparable to ApAP when administered in vivo.
 31. A method ofalleviating pain in a subject, the method comprising administering tosaid subject afflicted with pain a therapeutically effective amount ofthe analgesic compound of any one of claims 1-28.
 32. A method ofpreventing pain in a subject, the method comprising administering tosaid subject afflicted with pain a therapeutically effective amount ofthe analgesic compound of any one of claims 1-28.
 33. A method ofameliorating pain in a subject, the method comprising administering tosaid subject afflicted with pain a therapeutically effective amount ofthe analgesic compound of any one of claims 1-28.
 34. A method ofreducing the incidence of pain in a subject, the method comprisingadministering to said subject afflicted with pain a therapeuticallyeffective amount of the analgesic compound of any one of claims 1-28.35. A method of delaying the development of pain in a subject, themethod comprising administering to said subject afflicted with pain atherapeutically effective amount of the analgesic compound of any one ofclaims 1-28.
 36. A method of preventing the development of pain in asubject, the method comprising administering to said subject afflictedwith pain a therapeutically effective amount of the analgesic compoundof any one of claims 1-28.
 37. A method of palliating pain in a subject,the method comprising administering to said subject afflicted with paina therapeutically effective amount of the analgesic compound of any oneof claims 1-28.
 38. The method of any one of claims 31-37, wherein paincomprises neuropathic pain, nociceptive pain, or a combination thereof.39. The method of claim 38, wherein the neuropathic pain comprisespost-surgical pain, neuropathic pain, dental pain, ophthalmic pain,arthritic pain, post- and/or traumatic pain, or a combination thereof.40. The method of any one of claims 31-37, wherein the therapeuticallyeffective amount comprises a dose of about 10 μM to about 10 mM of thecomposition is administered to the subject.
 41. The method of claim 40,wherein the therapeutically effective amount comprises a dose of about50 μM to about 1 mM of the composition is administered to the subject.42. The method of any one of claims 31-37, wherein the compound isadministered in a single dose.
 43. The method of any one of claims31-37, wherein the compound is administered at intervals of about 4hours, 12 hours, or 24 hours.
 44. The method of any one of claims 31-37,wherein the composition is administered orally, parentally,transdermally, or nasally.
 45. The method of any one of claims 31-37,wherein the composition is administered in the form of a pill, capsule,cream, spray, lotion, or aqueous solution.
 46. The method of any one ofclaims 31-37, wherein the composition exhibits analgesia, antipyrisis,or a combination thereof.
 47. The method of any one of claims 31-37,wherein the composition reduces the risk of hepatoloxicity by at leastabout 20%.
 48. The method of any one of claims 31-37, further comprisingadministering concurrently or subsequently a therapeutically effectiveamount of an opioid and/or NSAID to the subject.
 49. The method of anyone of claims 31-37, wherein the composition is not metabolized toNAPQI.
 50. A medical kit for the treatment of pain, the kit comprising:printed instructions for administering the compound to the subjectafflicted with pain; an analgesic compound of any one of claims 1-28, ora pharmaceutical composition according to claims 1-28.